Cardiovascular diseases, coronary artery disease in particular, are a major cause of mortality worldwide. Genetically determined ethnic propensity of Asian Indians, growing urbanisation, changing lifestyle and increasing level of individual stress not only contributes to premature coronary artery disease but also accelerates the overall incidence of coronary artery disease in the subcontinent. Heart can be considered as a system of muscular mechanical pump with multiple chambers guarded by the valves and coordinated by spreading waves of electrical depolarization down the conduction pathways. Heart's ability to pump depends on its ability to sustain its own metabolic energy deriving procedures which are mostly aerobic and depends critically on coronary circulation; which is jeopardized in case of coronary artery disease and needs urgent revascularization measures including thrombolytic agents. In this setting of abnormal cardiac rhythm (arrhythmia), asynchrony and impaired cardiac contractility leads to heart failure. The left ventricle fails to pump adequately to maintain the tissue perfusion and to meet the metabolic demands of vital organs including brain and kidneys and heart failure ensues. Decreased stroke volume in heart failure leads to reflex rise to heart rate in order to maintain the minute volume which in turn again raises the metabolic demand of the cardiac myocytes further worsening the situation. Failure may progress slowly or can be acute and life threatening. “Sudden Cardiac Death” is a clinical entity with a grave prognosis as death occurs by definition within one hour from the onset of symptoms. (Braunwald E, Mock M B and Watson J. Eds. 1982. Congestive heart failure. Current Research and Clinical Applications. Grune and Stratton).
Medicinal application of the various fractions of snake venom is well known to humankind as depicted in the Ayurveda, Homoeopathy and Unani literatures. Clot resolving effect, anti-tumor effect and analgesic effect of the numerous biomolecules isolated from snake venom has been reported. From the present laboratory, a novel fibrinolytic peptide (Hannahpep) has been isolated from King Cobra venom Patent Application No: 2384/Del/98 dated 13.8.98). However isolation of any anti-arrhythmic or cardiotonic principles from snake venom is not reported till date. However, there is certain other animal venom components, which possess cardiotonic/anti-arrhythmic property. Reference may be made to:    DPI-201-206 (Romey G, Quart U, Pauron D, Frelin C, Renand J and Lazdunski M. 1987. Proc. Natl. Acad. Sci. USA, 84, 896–900) which is a sea-anemone venom toxin which has a positive inotropic combined with a negative chronotropic effect, action potential prolongation and coronary dilating activity.    Cardiopep (Vick J, Shipman W and Brooks R. 1974. Beta adrenergic and anti-arrhythmic effects of cardiopep, a newly isolated substance from whole bee venom. Toxicon, 12, 39–144) a cardioactive anti-arrhythmic substance has been found in bee venom. It has been shown to increase the rate and force of contraction of the heart.
The present invention relates to a process for isolation of an anti-arrhythmic component from King Cobra venom.
The major drawbacks of anti-arrhythmic drugs already in use are that a significant number of available positive inotropic agents have either very narrow margin between their therapeutic and toxic levels or require considerations for adjuvant pharmacological agents in order to antagonize their side effects. Cardiac glycosides for example have very high systemic toxicity and may induce cardiac rhythm abnormalities. Reference may be made to Goodman and Gilman's The Pharmacological basis of therapeutics. 8th Edition, 1990. Editors Nies A S, Rall T W, Taylor P, Goodman Gilman A, Pg. 854–857, 861, 863, 870.
The drugs, which improves myocardial contractility without raising the heart rate, free from or have minimal toxicity, and does not interfere with the coagulation but renormalizes the cardiac arrhythmia, would have been an effective agent of choice in treating the cardiac pathophysiological states.
Applicants, for the first time isolated and identified a novel low molecular weight biomolecule from the venom of snake King Cobra, which possesses anti-arrhythmic property. This novel compound had a λmax of 225.4 nm, Emax of 360 nm when excited at 250 nm and having a molecular weight of 256 Daltons. The novel anti-arrhythmic compound increased the force of contraction and successfully restored the hypodynamic heart and auricle, sparing any change in the heart rate.